Evaluation of Lenalidomide, Bortezomib, and Dexamethasone in Early Versus Standard Treatment of Multiple Myeloma Relapse from MRD Negativity

The primary objective of this study is to evaluate the efficacy of early treatment initiation in patients with **multiple myeloma** who exhibit minimal residual disease (MRD) negativity after standard induction, transplant, and consolidation therapy. Specifically, the study aims to determine if starting treatment at the first detection of malignant plasma cells in the bone marrow, as measured by MRD, can prolong progression-free survival (PFS) compared to the standard indication for relapse treatment according to International Myeloma Working Group (IMWG) guidelines. This is clinically relevant as it may offer insights into optimizing treatment timing to improve patient outcomes.

Secondary objectives include: Part 1 - assessing the progression-free survival (PFS) rate, overall survival (OS) rate, safety profile, and overall response rate (ORR) after four cycles of VRd consolidation treatment. Part 2 - determining the time from randomization to the start of third-line therapy (TTNT), the rate of MRD negativity during second-line treatment, the impact of early versus late treatment initiation on health-related quality of life (HRQOL), and evaluating safety through adverse events monitoring and relevant clinical laboratory parameters.

The clinical trial focuses on patients diagnosed with **multiple myeloma**, specifically targeting individuals eligible for high-dose therapy and autologous stem cell transplantation (ASCT). The study population includes both male and female participants aged between 18 and 75 years. Participants are required to have a measurable disease as defined by the International Myeloma Working Group, with specific criteria for serum monoclonal paraprotein levels or light chain multiple myeloma. The trial does not involve a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2, although those with a score of 3 may be included if the condition is caused by myeloma. The trial population was selected based on their ability to adhere to the study protocol and visit schedule, and all participants provided voluntary written informed consent. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the efficacy of early treatment initiation in patients with **multiple myeloma** who achieve minimal residual disease (MRD) negativity. This is a Phase II/III trial with a randomized, controlled, double-blind design. The trial aims to determine whether starting treatment at the first sign of malignant plasma cells in the bone marrow, as measured by MRD, prolongs progression-free survival compared to standard relapse treatment guidelines. The trial is expected to conclude by September 2032, with recruitment starting in August 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease status, and performance score. The trial is divided into two parts. Part 1 involves patients with newly diagnosed multiple myeloma eligible for high-dose therapy and autologous stem cell transplant (ASCT). Part 2 includes patients who have achieved complete response and MRD negativity after first-line therapy. Follow-up visits will be scheduled to monitor disease progression, adverse events, and treatment response, with MRD assessments conducted at specified intervals. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination.

Participant involvement is expected to last up to 120 days for those receiving **lenalidomide** and up to 50 days for those on **carfilzomib** or **daratumumab**. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. The trial will utilize various pharmaceutical forms, including oral capsules, subcutaneous injections, and intravenous administration, to deliver the investigational products. The primary endpoints include the number of patients achieving MRD negativity and progression-free survival rates, while secondary endpoints focus on overall survival, time to next treatment, and patient-reported outcomes.

The clinical trial involves the administration of several **experimental medications**. **Lenalidomide Mylan** is provided in the form of 25 mg hard capsules. The active substance, **lenalidomide**, is of chemical origin. The medication is administered orally with a maximum daily dose of 25 mg, and the treatment period can extend up to 120 days. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Bortezomib Accord** is supplied as a 3.5 mg powder for solution for injection. The active substance, **bortezomib**, is also of chemical origin. This medication is administered via subcutaneous injection with a maximum daily dose of 2.6 mg/m². The treatment duration is limited to 8 days, and dosing schedules are strictly followed to maintain consistency in administration.

**Carfilzomib** is administered through intravenous administration. The active substance, **carfilzomib**, is chemically derived. The maximum daily dose is 70 mg/m², with a total dose not exceeding 140 mg/m² over a treatment period of 50 days. The administration is carefully monitored to ensure accurate dosing and participant safety.

**Dexametason Abcur** is available in 1 mg tablets, with **dexamethasone** as the active chemical substance. This medication is taken orally, with a maximum daily dose of 40 mg. The treatment period is set for 50 days, and participant adherence is tracked through regular follow-ups and pill counts.

**Daratumumab** is administered as a subcutaneous injection. The active substance, **daratumumab**, is a protein of other origin. The maximum daily dose is 1800 mg, with the treatment period extending up to 50 days. Compliance is ensured through scheduled visits and monitoring of injection administration.

Throughout the trial, participant compliance is closely monitored through scheduled visits, adherence checks, and regular assessments to ensure the integrity of the study and the safety of the participants. The trial aims to evaluate the efficacy and safety of these treatments in achieving the study's objectives.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Part 1 include the number of patients achieving **Minimal Residual Disease (MRD)** negativity, measured by Euroflow, at 30-45 days after the initiation of the fourth cycle of consolidation therapy. For Part 2, the primary endpoints are the progression-free survival (PFS) rate and overall survival (OS) rate of Arm A (MRD guided) compared to Arm B, defined as the time from randomization to disease progression or death due to any cause following second-line treatment.

Secondary endpoints for Part 1 include the PFS and OS rates of patients receiving four cycles of VRd as consolidation therapy, the number of adverse events (AEs) and relevant laboratory parameters monitored at every visit, and the proportion of patients achieving partial response (PR) or better following the consolidation treatment. In Part 2, secondary endpoints include the time from randomization to the start of third-line therapy (TTNT), the proportion of patients achieving MRD negativity during second-line treatment, patient-reported outcomes on health-related quality of life (HRQOL) forms, and the number of AEs. MRD negativity will be monitored using Euroflow at 6 and 18 months in Arm A, and after achieving complete response (CR) in Arm B, with the first MRD testing occurring after 6 months.